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Well the title may not reflect exactely the thread, it is about the effect of sex hormons on deiodinases activity and T4/T3 ratio...:)


The effects of sex-steroid administration on the pituitary–thyroid axis in transsexuals


Estrogen and androgen administration modulate the pituitary-thyroid axis through alterations in thyroid hormone-binding globulin (TBG) metabolism, but the effects of sex steroids on extrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion in humans are unknown.

We studied 36 male-to-female and 14 female-to-male euthyroid transsexuals at baseline and after 4 months of hormonal treatment.

Male-to-female transsexuals were treated with cyproterone acetate (CA) 100 mg/day alone (n = 10)
or in combination with either oral ethinyl estradiol (or-EE) 100 microg/day (n = 14)
or transdermal 17beta-estradiol (td-E) 100 microg twice a week (n = 12).

Female-to-male transsexuals were treated with i.m. testosterone 250 mg twice a week. A t-test was used to test for differences within groups and ANOVA with post hoc analysis to test for differences between the groups.


Or-EE increased TBG (100 +/- 12%, P < .001) and testosterone decreased TBG (-14 +/- 4%, P = 0.01), but free T4 did not change. Td-E and CA did not affect TBG concentrations.

TSH was not different between groups at baseline or after treatment.

CA decreased T3/T4 ratios (-9 +/- 3%, P = 0.04), suggesting that T4 to T3 conversion was lower.

Testosterone increased T3/T4 ratios (30 +/- 9%, P = 0.02), which probably reflects higher T4 to T3 conversion.

Oral but not transdermal estradiol increases TBG, whereas testosterone lowers TBG.
Testosterone increases T3/T4 ratios.
Estradiol does not affect T3/T4 ratios, irrespective of the route of administration.

from the full article:

"sex hormones also affect deiodinase activity. Peripheral conversion of inactive T4 to biologically active tri- iodothyronine (T3 ) is catalyzed by 5 0 -deiodinase activity and is the main source of circulating T3 . Two of the three deiodinase subtypes, type 1 (D1) and 2 (D2), have 5'-deiodinase capability. D1 is expressed in the liver of rodents and humans. D2 is expressed in brown adipose tissue of rodents and in muscle of humans. It was recently shown that muscle D2 activity is the major source of circulating T3 in euthyroid humans (4). In rats, hepatic activity of 5'-deiodinase was not altered by ovariectomy (5), but increased after a supraphysiological dose of 17 b -estradiol (6). The latter effect was blunted by concurrent administration of progestins (6). In orchidectomized rats, hepatic D1 activity was reduced, but could be restored to normal by the substitution of testosterone (5,6).
These observations suggest that physiological concentrations of testosterone stimulate D1 activity in male rats and might provide an explanation for higher D1 activity in the liver of normal male rats than in female rats.
The effects of androgens and estrogens on 5'- deiodinase activity in humans are not known. For evident reasons, 5'-deiodinase activity cannot be measured as easily in humans as in rodents, but serum T3 /T4 ratios can be used as a marker for 5'-deiodinase activity, since the majority of circulating serum T3 is produced by peripheral conversion of T4 to T3 .


CA is a progestin with anti-androgenic action by competitive binding to the testosterone receptor.


Testosterone administration increased T3 /T4 ratios, indicating increased 5'-deiodinase activity, whereas CA decreased T3 /T4 ratios, suggesting a decreased activity of 5'-deiodinase.
Oral or transdermal estrogen administration, combined with CA, had no effect on T3 /T4 ratios. Plasma T3 /T4 ratios may be used as a marker of extrathyroidal T4 to T3 conversion, but several assumptions have to be met:
(i) Steady state is achieved: sex-steroid administration alters TBG concentrations. As a result, under
non-steady state conditions, the availability of free T4 and T3 for deiodination could fluctuate, resulting in different T3 /T4 ratios independent of 5'-deiodinase activity. However, it seems safe to assume that steady state was achieved, since we studied the subjects after 8 weeks of sex-steroid administration, which is more than five times the half-life of T4 and TBG

(ii) The ratio of thyroidal T3 to T4 secretion is constant : different plasma T3 /T4 ratios could just reflect changed T3 /T4 secretion ratios. Various conditions influence thyroidal T3 /T4 secretion ratios. Iodine deficiency results in preferential excretion of T3 and consequently lower T3 /T4 secretion and plasma ratios. During transition from euthyroidism to hypothyroidism, T4 decreases before T3 and vice versa for hyperthyroidism. Neither of these conditions, iodine deficiency nor dysthyroidism, were present in our study subjects

(iii) Deiodinase type 3 (D3) activity is constant: recently, D3 tissue distribution in humans has been characterized (11, 12), but the regulation of D3 activity in humans is largely unknown. Because of this lack of information on D3 regulation, there is currently no basis to support or reject the third assumption. (iv) Plasma T3 and T4 concentrations reflect tissue concentrations: disproportionate T3 /T4 ratios in tissue and plasma would invalidate the plasma T3 /T4 ratio as an indicator of peripheral T4 to T3 conversion, but it was recently shown that plasma T3 and T4 concentrations correlate closely to liver and muscle concentrations (13).

In humans plasma T 3 comes from two, relatively independent sources, namely thyroid secretion and extrathyroidal conversion of T 4 by 5'-deiodinase with a relative contribution of 20 and 80% respectively (20). Three types of deiodinase exist, but only D1 and D2 have 5'-deiodinase capability. In euthyroid humans, the relative contributions of D1 and D2 to extrathyroidal T3 production are approximately 34 and 66% (4). The effects of sex steroids on 5'-deiodinase activity have thus far only been studied in rats, but thyroid hormone metabolism in rats is markedly different from humans. In rats, thyroid secretion accounts for 40% of plasma T3 and extrathyroidal 5'-deiodination of T4 by D1 and D2, each for 30%. In rats, D2 is not expressed in muscle and contributes significantly less to plasma T3 as compared to humans. Only a limited number of studies (summarized in the Introduction) have studied the effects of sex hormones in rats on D1 activity in the liver.
Low-dose estrogens did not affect hepatic D1 activity, whereas testosterone increased D1 activity. Currently, there is no evidence to support an effect of androgens or estrogens on D2 activity, but the data are limited to D2 activity in the rat pituitary (6) and the mouse bone (21).
Whether testosterone increased T4 to T3 conversion by effects on D1 or D2 remains speculative.
CA decreased T3 /T4 ratios suggesting decreased T4 5'-deiodination.
The effect of CA on T3 /T4 ratios could be induced by the anti-androgenic effect, but also by the progestinic effect of CA.
In rats progestin decreased hepatic and pituitary D1 activity (6). Unfortunately, we could only study the effects of estrogens with concurrent CA administration. There- fore, we cannot exclude that a potential effect of estrogens was blunted by CA.